US6716433B1 - Group a streptococcal vaccines - Google Patents
Group a streptococcal vaccines Download PDFInfo
- Publication number
- US6716433B1 US6716433B1 US09/151,409 US15140998A US6716433B1 US 6716433 B1 US6716433 B1 US 6716433B1 US 15140998 A US15140998 A US 15140998A US 6716433 B1 US6716433 B1 US 6716433B1
- Authority
- US
- United States
- Prior art keywords
- group
- streptococcal
- immunogenic
- fusion polypeptide
- protein
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
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- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Definitions
- the present invention provides pharmaceutical compositions and methods, and in particular, vaccines for use in preventing Group A streptococcal infections.
- Streptococci are a group of bacteria with the capacity to grow in chains. Many varieties are part of the normal bacterial flora in humans and are not especially harmful. However, a particular group of streptococcal bacteria, called group A and represented by Streptococcus pyogenes, is a human pathogen. Briefly, group A streptococci cause a variety of human illnesses, ranging from uncomplicated pharyngitis and pyoderm a to life-threatening infections associated with toxic shock syndrome, deep tissue invasion and sepsis. In some individuals, untreated streptococcal pharyngitis may be followed by acute rheumatic fever.
- streptococcal infections can be generally treated with antibiotics, in at least 4% of cases the infection leads to acute rheumatic fever. This disease is particularly prevalent in developing countries such as India, where millions of school-age children are affected.
- the present invention provides a new Group A streptococcal vaccines with enhanced immunogenicity, and further, provides other related advantages.
- the present invention provides immunogenic synthetic fusion polypeptides which stimulate an immune response against Group A streptococci.
- such polypeptides comprise (a) at least two immunogenic polypeptides from a Group A streptococci of at least 10 amino acids in length which are capable of stimulating an immune response against Group A streptococci, and a peptide C terminal to the immunogenic polypeptide which protects the immunogenicity of the immunogenic portion.
- the C-terminal peptide is not required to stimulate an immune response against Group A streptococci and hence, may be an inconsequential non-immunogenic peptide, or a reiterated immunogenic polypeptide.
- the immunogenic polypeptide can be obtained from a wide variety of Group A streptococci (ranging from “1” to greater than “90”), including for example, Types 1, 1.1, 2, 3, 4, 5, 6, 11, 12, 13, 14, 18, 19, 22, 24, 28, 30, 48, 49, 52, 55 and 56.
- vaccinating agents for promoting an immune response against Group A streptococci, comprising (a) at least two immunogenic polypeptides from a Group A streptococci of at least 10 amino acids in length which are capable of stimulating a protective immune response against Group A streptococci, and (b) a peptide C terminal to the immunogenic polypeptide which protects the immunogenicity of the immunogenic portion, wherein the C-terminal peptide is not required to stimulate an immune response against Group A streptococci.
- the polypeptide may be selected from a wide variety of Group A streptococci (ranging from “1” to greater than “90”), including for example, types 1.1, 2, 3, 4, 5, 6, 11, 12, 13, 14, 18, 19, 22, 24, 28, 30, 48, 49, 52, 55 and 56.
- the vaccinating agent may further comprise an adjuvant, such as, for example, alum, Freund's adjuvant, and/or an immunomodulatory cofactor e.g., (IL-4, IL-10, ⁇ -IFN, or IL-2, IL-12 or IL-15).
- an adjuvant such as, for example, alum, Freund's adjuvant, and/or an immunomodulatory cofactor e.g., (IL-4, IL-10, ⁇ -IFN, or IL-2, IL-12 or IL-15).
- FIG. 1 is a schematic of the hexavalent vaccine indicating the length of each emm gene fragment and the restriction sites that were synthesized into the original PCR primers.
- Each of the emm gene fragments starts at the first codon that encodes the mature native protein except the emm3 fragment, which represents codons 21-70.
- FIG. 2 is a SDS-polyacrylamide gel electrophoresis of the purified hexavalent protein stained with CoomassieTM blue.
- Computer-assisted image analysis of the stained protein bands indicated that the hexavalent protein (M.W. 45 kDa) accounted for 86% to 89% of the total protein in each sample.
- FIGS. 3A and 3B are ELISA's of antisera from three rabbits immunized with the hexavalent vaccine in either alum or CFA. Titers are expressed as the inverse of the last dilution of serum that resulted in an O.D. of >0.1.
- the ELISA antigen was the purified hexavalent protein. Each symbol represents serum from one rabbit.
- FIGS. 4A-4F and ELISA's of antisera from rabbits immunized with the hexavalent protein in alum Titers were determined using the purified pepsin-extracted M proteins (pep M) from the respective serotypes of group A streptococci. Each symbol represents one of three immunized rabbits.
- FIG. 5 depicts in vitro opsonization assays of antisera from rabbits immunized with the hexavalent protein in alum.
- Rotation mixtures consisted of the test organism, 0.1 ml of immune serum, and 0.4 ml of nonimmune human blood. The mixture was rotated for 45 minutes and the percentage of PMNs that had ingested or were associated with streptococci was estimated by microscopic counts of stained smears. In each assay, the preimmune serum resulted in ⁇ 10% percent opsonization. Each different bar represents serum from one of the three immunized rabbits.
- FIG. 6 is a graph which depicts opsonization of different strains within the same serotype of group A streptococci promoted by hexavalent rabbit antisera. Each symbol represents a strain of group A streptococci of the serotype indicated on the horizontal axis. Opsonization assays were performed as described below in the Examples.
- FIGS. 7A and 7B show a nucleic acid sequence (SEQ ID NO:15) and predicted amino acid sequence (SEQ ID NO:16) of a hexavalent M protein vaccine.
- Vaccinating Agent refers to a composition which is capable of stimulating a protective immune response within the host which receives the vaccinating agent.
- the vaccinating agent may be either protein, or, DNA-based (e.g., a gene delivery vehicle).
- a prokaryotic host may be generated to be a vaccinating agent, and designed to express an immunogenic polypeptide or multivalent construct of the present invention (see, e.g., U.S. application Ser. No. 07/540,586).
- Gene delivery vehicle refers to a recombinant vehicle, such as a recombinant viral vector, a nucleic acid vector (such as plasmid), a naked nucleic acid molecule such as genes, a nucleic acid molecule complexed to a polycationic molecule capable of neutralizing the negative charge on the nucleic acid molecule and condensing the nucleic acid molecule into a compact molecule, a nucleic acid associated with a liposome (Wang et al., PNAS 84:7851, 1987), a bacterium, and certain eukaryotic cells such as a producer cell, that are capable of delivering a nucleic acid molecule having one or more desirable properties to host cells in an organism.
- a recombinant viral vector such as plasmid
- a naked nucleic acid molecule such as genes
- a nucleic acid molecule complexed to a polycationic molecule capable of neutralizing the negative charge on the nucleic acid
- the present invention provides vaccinating agents suitable for preventing Group A streptococcal infections. Briefly, as described in more detail below it has bee discovered that, in order to optimize the immunogenicity of all aspects of a multivalent vaccine.
- immunogenic synthetic fusion polypeptides which stimulate an immune response against Group A streptococci are provided.
- Such polypeptides generally comprise (a) at least two immunogenic polypeptides from a Group A streptococci of at least 10 amino acids in length which are capable of stimulating an immune response against Group A streptococci, and (b) a peptide C terminal to the immunogenic polypeptide which protects the immunogenicity of the immunogenic portion, wherein the C-terminal peptide is not required to stimulate an immune response against Group A streptococci.
- Particularly preferred protective peptides are generally at least ten amino acids in length, and may be 30 amino acids or longer.
- Immunogenic polypeptides suitable for use within the present invention may be readily identified and generated given the disclosure of the subject application (see also Dale and Beachey, J. Exp. Med. 163:1191-1202; 1986; Beachey et al., Nature 292:457-459, 1981; Dale et al., J. Immunol. 151:2188-2194; 1993; and U.S. Pat. Nos. 4,454,121; 4,521,334; 4,597,967; 4,705,684; 4,919,930; and 5,124,153).
- Particularly preferred polypeptides can be obtained within the 50 amino acid residues of the N-terminus of an M protein.
- Serotypes of Group A streptococci can be readily obtained from clinical isolates, from university collections (e.g., Rockefeller University Collection, 1230 York Avenue, New York, N.Y.) or from depositories such as the American Type Culture Collection (1080 University Boulevard, Manassas, Va.). Furthermore, sequence for Group A streptococci serotypes are available from the Centers for Disease Control, Atlanta, Ga.
- peptides are copied from various serotypes (e.g., the amino-terminal 20-50 amino acids of M5 (Beachey et al., “Purification and properties of M protein extracted from group A streptococci with pepsin. Covalent structure of the amino terminal region of the type 24 M antigen,” J. Exp. Med. 145:1469-1483, 1977).
- Additional sarcolemmal membrane crossreactive epitopes are localized to peptide 164-197.
- M5 copies of M5 that evoked antibodies that crossreacted with articular cartilage and synovium can also be found within the B repeats and the region spanning the A and B repeats of M5.
- the brain-crossreactive epitopes of M6 that were shared with other M proteins are localized to the B repeat region of the molecule.
- tissue-crossreactive epitopes are shared among types 5, 6, 18 and 19 M proteins (Bronze, M. S. and Dale, J. B., “Epitopes of streptococcal M proteins that evoke antibodies that cross-react with human brain,” J. Immunol. 151:2820-2828, 1993).
- Primary structural data reveals that all of thee M proteins contain similar sequences within their B repeats (Dale et al., “Recombinant tetravalent group A streptococcal M protein vaccine,” J. Immunol.
- tissue-specific epitope it is not necessary to localize the tissue-specific epitope, but rather, to first localize protective epitopes and ensure that they are not tissue-reactive.
- a suitable immunogenic polypeptide for a selected serotype may be, optionally, combined with immunogenic polypeptides from other serotypes, in order to construct a multivalent vaccine.
- preferred vaccines include vaccines developed from a combination of serotypes such as 1, 1.1, 2, 3, 4, 5, 6, 11, 12, 13, 14, 18, 19, 22, 24, 28, 30, 48, 49, 52 and 56 (for serotype 30 see Nakashima et al., Clinic Infec. Dis. 25:260, 1997).
- Representative examples include vaccine such as 24, 5, 6, 19, 1, 3, X; and 1, 3, 5, 6, 18, 19, 22, 24, 28, 30, and X, wherein X is the C-terminal protective polypeptide.
- Vaccinating agents of the present invention can be synthesized chemically (see, e.g., Beachey et al., Nature 292:457-459, 1981), or generated recombinantly.
- PCR primers can be synthesized to amplify desired 5′sequences of each emm gene, and each primer is extended to contain a unique restriction enzyme site used to ligate the individual PCR products in tandem.
- the C-terminal portion of the vaccinating agent is constructed so as to contain a selective portion that can be lost or cleaved in vivo without affecting the efficacy of the vaccine. This may be accomplished by, for example, including an inconsequential non-immunogenic polypeptide at the end, or, including an immunogenic polypeptide that does not adversely impact the efficiency of the vaccine (e.g., a reiterated immunogenic polypeptide may be included at the end of the vaccine).
- protective antigens from unrelated pathogens can also be combined into a single polypeptide, which may circumvent the need for carriers.
- Vaccines against some pathogens might include T and B cell epitopes originally derived from different proteins on the same hybrid construct. Additionally, multivalent hybrid proteins may be sufficient conjugates in carbohydrate vaccines, such as those for S. pneumonia, H. influenza B or group B streptococci.
- the multivalent genes are ligated into any suitable replicating plasmid which is used to transform an appropriate prokaryote host strain.
- Prokaryotes include gram negative or gram positive organisms, for example E. coli or bacilli.
- Suitable prokaryotic hosts cells for transformation include, for example, E. coli, Bacillus subtilis, Salmonella typhimurium, and various other species within the genera Pseudomonas, Streptomyces, and Staphylococcus.
- Expression vectors transfected into prokaryotic host cells generally comprise one or more phenotypic selectable markers such as, for example, a gene encoding proteins that confer antibiotic resistance or that supplies an auxotrophic requirement, and an origin of replication recognized by the host to ensure amplification within the host.
- Other useful expression vectors for prokaryotic host cells include a selectable marker of bacterial origin derived from commercially available plasmids. This selectable marker can comprise genetic elements of the cloning vector pBR322 (ATCC 37017). Briefly, pBR322 contains genes for ampicillin and tetracycline resistance and thus provides simple means for identifying transformed cells.
- the pBR322 “backbone” sections are combined with an appropriate promoter and a mammalian ETF structural gene sequence.
- Other commercially available vectors include, for example, pKK223-3 (Pharmacia Fine Chemicals, Uppsala, Sweden), pEQ30 (6xHis-tag expression vector), and pGEM1 (Promega Biotec, Madison, Wis., USA).
- Common promoter sequences for use within prokaryotic expression vectors include ⁇ -lactamase (penicillinase), lactose promoter system (Chang et al., Nature 275:615, 1978; and Goeddel et al., Nature 281:544, 1979), tryptophan (trp) promoter system (Goeddel et al., Nucl. Acids Res. 8:4057, 1980; and EPA 36,776) and tac promoter (Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, (1989)).
- a particularly useful prokaryotic host cell expression system employs a phage ⁇ P L promoter and a c1857ts thermolabile repressor sequence.
- Plasmid vectors available from the American Type Culture Collection that incorporate derivatives of the ⁇ P L promoter include plasmid pHUB2 (resident in E. coli strain JMB9 (ATCC 37092)) and pPLc28 (resident in E. coli RR1 (ATCC 53082)).
- Transformation of the host strains of E. coli is accomplished by electroporation using standard methods (Dale et al., “Recombinant tetravalent group A streptococcal M protein vaccine,” J. Immunol. 151:2188-2194, 1993; Dale et al., “Recombinant, octavalent group A streptococcal M protein vaccine,” Vaccine 14:944-948, 1996).
- Successful transformants are identified by colony blots using rabbit antisera raised against one of the native M proteins or a synthetic peptide copy of the amino-terminus of one of the M proteins included in the multivalent protein.
- the molecular size and antigenicity of the recombinant protein expressed by selected clones are determined by performing Western blots of extracts of E. coli (Dale et al., “Recombinant tetravalent group A streptococcal M protein vaccine,” J. Immunol. 151:2188-2194, 1993) using rabbit antisera raised against each native M protein purified form pepsin extracts of live streptococci (Beachey et al., “Purification and properties of M protein extracted from group A streptococci with pepsin: Covalent structure of the amino terminal region of the type 24 M antigens,” J. Exp. Med. 145:1469-1483, 1977).
- the multivalent gene is sequenced by the dideoxy-nucleotide chain termination method to confirm that each gene fragment is an exact copy of the native emm sequence.
- the M protein vaccines described above are ideally suited for delivery via naked DNA because protective immunity is ultimately determined by antibodies.
- the multivalent genes are ligated into plasmids that are specifically engineered for mammalian cell expression (see, e.g., Hartikka et al., Hum Gene Ther 7:1205-17, 1996, which contains the promoter/enhancer element from cytomegalovirus early gene, the signal peptide from human tissue plasminogen activator and a terminator element from the bovine growth hormone gene).
- the M protein hybrid genes can be cloned into the plasmid which is used to transfect human cell lines to assure recombinant protein expression.
- the plasmid is propagated in E.
- mice are immunized with 50 ug of plasmid in 50 ul saline given intramuscularly into the rectus femoris. Booster injections of the same dose are given at three and six weeks after the initial injection.
- a wide variety of other gene delivery vehicles can likewise be utilized within the context of the present invention, including for example, viruses, retrotransposons and cosmids.
- Representative examples include adenoviral vectors (e.g., WO 94/26914, WO 93/91919; Yei et al., Gene Therapy 1:192-200, 1994; Kolls et al., PNAS 91(1):215-219, 1994; Kass-Eisler et al., PNAS 90(24):11498-502, 1993; Guzman et al., Circulation 88(6):2838-48, 1993; Guzman et al., Cir. Res.
- Gene-delivery vehicles may be introduced into a host cell utilizing a vehicle, or by various physical methods. Representative examples of such methods include transformation using calcium phosphate precipitation (Dubensky et al., PNAS 81:7529-7533, 1984), direct microinjection of such nucleic acid molecules into intact target cells (Acsadi et al., Nature 352:815-818, 1991), and electroporation whereby cells suspended in a conducting solution are subjected to an intense electric field in order to transiently polarize the membrane, allowing entry of the nucleic acid molecules.
- nucleic acid molecules linked to an inactive adenovirus include the use of nucleic acid molecules linked to an inactive adenovirus (Cotton et al., PNAS 89:6094, 1990), lipofection (Felgner et al., Proc. Natl. Acad. Sci. USA 84:7413-7417, 1989), microprojectile bombardment (Williams et al., PNAS 898:2726-2730, 1991), polycation compounds such as polylysine, receptor specific ligands, liposomes entrapping the nucleic acid molecules, spheroplast fusion whereby E.
- coli containing the nucleic acid molecules are stripped of their outer cell walls and fused to animal cells using polyethylene glyucol, viral transduction, (Cline et al., Pharmac. Ther. 29:69, 1985; and Friedmann et al., Science 244:1275, 1989), and DNA ligand (Wu et al, J. of Biol. Chem. 264:16985-16987, 1989), as well as psoralen inactivated viruses such as Sendai or Adenovirus.
- Serum from mice immunized with gene delivery vehicles containing multivalent M protein genes are assayed for total antibody titer by ELISA using native M proteins as the antigen. Serum opsonic antibodies are assayed as described above.
- Protective efficiacy of DNA M protein vaccines is determined by direct mouse protection tests using the serotypes of group A streptococci represented in the vaccine.
- vaccinating agents can be administered to a patient by a variety of routes, including for example, by intramuscular, subcutaneous, and mucosal routes.
- the vaccinating agent may be administered as a single dosage, or in multiple units over an extended period of time.
- the vaccinating agent is administered to a human at a concentration of 50-300 ug per singe site intramuscular injection. Several injections can be given (e.g., three or four) at least one month apart in order to further increase vaccine efficacy.
- the vaccinating agent will be administered in the form of a pharmaceutical composition
- a pharmaceutical composition comprising purified polypeptide in conjunction with physiologically acceptable carriers, excipients or diluents.
- Such carriers will be nontoxic to patients at the dosages and concentrations employed.
- the preparation of such compositions entails combining the vaccinating agent with buffers, antioxidants such as ascorbic acid, low molecular weight (less than about 10 residues) polypeptides, proteins, amino acids, carbohydrates including glucose, sucrose or dextrans, chelating agents such as EDTA, glutathione and other stabilizers and excipients.
- Neutral buffered saline or saline mixed with conspecific serum albumin are exemplary appropriate diluents.
- the vaccinating agent is combined with an adjuvant, such as, for example, Freund's adjuvant, alum and the like.
- an adjuvant such as, for example, Freund's adjuvant, alum and the like.
- a hexavalent emm gene was constructed using PCR to amplify specific 5′ regions of six different emm genes (24, 5, 6, 19, 1 and 3) essentially as described previously (Dale et al., “Recombinant tetravalent group A streptococcal M protein vaccine,” J. Immunol. 151:2188-2194, 1993; Dale et al., “Recombinant, octavalent group A streptococcal M protein vaccine,” Vaccine 14:944-948, 1996).
- the multivalent genes are constructed using PCR and primers that specify specific 5′ emm gene fragments.
- the gene fragments may range in size from 30 bp to 300 bp.
- Chromosomal DNA from each serotype of group A streptococcus is used as the template for the PCR reactions.
- the PCR primers are as follows:
- PCR is performed on the chromosomal template as previously described (Dale et al., “Recombinant tetravalent group A streptococcal M protein vaccine,” J. Immunol. 151:2188-2194, 1993). To assure ligation of the fragments in the correct orientation and reading frame, each PCR product is purified, ligated, and then subjected to PCR again using the forward primer from the 5′ fragment and the reverse primer from the 3′ fragment. For example, to construct a hexavalent emm gene containing DNA sequences from types 24, 5, 6, 19, 1 and 3 M proteins, the M24 and M5 gene fragments are amplified by PCR using the primers described above.
- PCR products are purified from agarose gels, cut with the appropriate restriction enzyme, and ligated together (Dale et al., “Recombinant tetravalent group A streptococcal M protein vaccine,” J. Immunol. 151:2188-2194, 1993; Dale et al., “Recombinant, octavalent group A streptococcal M protein vaccine,” Vaccine 14:944-948, 1996).
- the ligation mixture is then amplified by PCR using the forward M24 primer and the reverse M5 primer.
- the resulting product of the appropriate size is then purified and ligated to the M6 and M19 gene fragment that was similarly constructed.
- the entire gene is amplified again by PCR, cut with the appropriate restriction enzymes and ligated into a suitable expression vector.
- the plasmid was purified from the host E. coli and a new PCR product from emm 24 was force cloned into the 3′ PstI restriction site.
- the hexavalent gene was sequenced by the dideoxy-nucleotide chain termination method to confirm that each gene fragment was an exact copy of the respective native emm sequence.
- Transformed E. coli were grown in a shaking incubator to log phase in 11 of LB containing 100 ⁇ g/ml ampicillin and 25 ⁇ g/ml kanamycin. IPTG (2 mM) was added for the final four hours of growth.
- the cell pellet was suspended in 30 ml PBS and lysed in a French pressure cell at 1000 psi.
- the hexavalent protein was purified from the supernatant using Ni-NTA resin according to the protocol provided by the manufacturer (Qiagen, Valencia, Calif.).
- the elution buffer containing the protein was concentrated from 15 ml to 5 ml in a spin filter (ULTRAFREE®-15, Millipore).
- the structure of the hybrid emm gene was confirmed by double-stranded sequencing methods after ligation into pQE30.
- the sequence of each subunit was identical to the respective native emm gene (FIG. 1 ).
- the fragments were joined only by two amino acids specified by each unique restriction site used to facilitate their ligation (FIG. 1 ).
- the purified hexavalent protein migrated on SDS-polyacrylamide gels with an apparent M.W. of 45 kDa. (FIG. 2 ).
- Gel scan analysis revealed that the intact hexavalent protein accounted for approximately 90% of the total stainable protein in the gel.
- Western blots using antisera against pep M24 showed that the majority of the remaining protein bands were immunoreactive and most likely were fragments of the hexavalent protein (data not shown).
- hexavalent vaccine either precipitated with alum or emulsified in complete Freund's adjuvant.
- the hexavalent protein 200 ⁇ g/ml
- aluminum hydroxide 2 mg/ml
- the hexavalent protein was also emulsified in CFA at a final concentration of 100 ⁇ g/ml.
- Rabbits that received the hexavalent vaccine in alum were given 100 ⁇ g i.m.
- the second set of rabbits received 100 ⁇ g of hexavalent vaccine in CFA subcutaneously as an initial injection and then booster injections of the same dose is saline were given at 4 and 3 weeks. Blood was obtained prior to the first injection and at 2-week intervals thereafter.
- ELISAs were performed using purified native pepsin-extracted M proteins (Beachey et al., “Purification and properties of M protein extracted from group A streptococci with pepsin: Covalent structure of the amino terminal region of the type 24 M antigen,” J. Exp. Med. 145:1469-1483, 1977) or the purified hexavalent protein, as previously described (Dale et al., “Heterogeneity of type-specific and cross-reactive antigenic determinants within a single M protein of group A streptococci,” J. Exp. Med. 151:1026-1038, 1980).
- Opsonic antibodies were detected by in vitro opsonization assays and indirect bactericidal assays (Beachey et al., “Human immune response to immunization with a structurally defined polypeptide fragment of streptococcal M protein,” J. Exp. Med. 150:862-877, 1979).
- ELISA titers are defined as the inverse of the last dilution of antisera resulting in an OD of >0.1 at 450 nm.
- the titers of immune sera against the native M antigen are most likely to predict the levels of antibodies that are evoked by the recombinant protein that will react with the M protein on the surface of the respective serotype of streptococcus (i.e. promote opsonization).
- Opsonic M protein antibodies correlate with protection against infection with the same serotype of group A streptococci (Lancefield, R. C., “Current knowledge of the type specific M antigens of group A streptococci,” J. Immunol. 89:307-313, 1962; Lancefield, R. C., “Persistence of type-specific antibodies in man following infection with group A streptococci,” J. Exp. Med. 110:271-282, 1959).
- Two related in vitro assays are used to detect opsonic antibodies in immune sera.
- the first is a screening assay that measures opsonization in mixtures of immune serum, whole, nonimmune human blood and the test organism (Beachey et al., “Purification and properties of M protein extracted from group A streptococci with pepsin: Covalent structure of the amino terminal region of the type 24 M antigen,” J. Exp. Med. 145:1469-1483, 1977).
- 0.1 ml of test serum is added to a standard number of bacteria and incubated for 15 minutes at room temperature.
- 0.4 ml of lightly heparinized human blood is added and the entire mixture is rotated end-over-end at 37° C. for 45 minutes.
- smears are prepared on microscope slides that are air-dried and stained with Wright's stain. “Percent opsonization” is quantitated by counting the percentage of polymorphonuclear leukocytes that have ingested or are associated with bacteria. An interpretable assay must have a preimmune control value that is 10% opsonization or less.
- Protective efficacy of M protein vaccines is determined by either indirect or direct (passive or active immunization) mouse protection tests. Indirect tests are performed by giving mice 1 ml of immune or preimmune serum via the intraperitoneal (i.p.) route 24 hours prior to challenge infections with the test organism given i.p. (Beachey et al., “Human immune response to immunization with a structurally defined polypeptide fragment of streptococcal M protein,” J. Exp. Med. 150:862-877, 1979). For each test organism, groups of 25 mice receive either preimmune or immune serum. The animals are then divided into 5 groups of 5 mice each and 10-fold increasing challenge doses of virulent streptococci are given to each subgroup. After 7 days of observation, the 50% lethal dose (LD 50 ) is calculated for each serotype tested.
- LD 50 50% lethal dose
- mice are actively immunized with M protein vaccine prior to the challenge infections.
- Each mouse receives 25-50 ug vaccine in alum give intramuscularly (i.m.) at time 0, 4 weeks, and 8 weeks.
- Challenge infections are performed ten weeks after the first injection.
- Control animals are sham immunized with alum alone.
- the LD50 is calculated and significance is determined using Fisher's exact test.
- mice were immunized with the vaccine adsorbed to ALUM and then challenged with two of the serotypes represented in the vaccine.
- Female outbred white Swiss mice were immunized via the i.m. route in the hind leg according to the following schedule: time 0, 25 ⁇ g; 3 weeks, 25 ⁇ g; 6 weeks, 50 ⁇ g; and 13 weeks, 50 ⁇ g.
- Challenge experiments were performed on the 20 immunized mice and 20 control, unimmunized mice (Table 1).
- the challenge strains were types 24 and 19, with the reasoning that the M24 peptide is the largest fragment in the hexavalent protein and is reiterated and the M19 fragment is one of two that are only 35 amino acids long. These two fragments should reflect the range of protective immunogenicity of the hexavalent protein.
- Intraperitoneal challenge of mice with virulent streptococci is the most stringent laboratory assay for opsonic antibodies.
- mice were challenged with an inoculum that approximated the LD 70 -LD 100 for each serotype, which was 2 ⁇ 10 4 CFU.
- the challenge experiments were begun 15 weeks after the first dose of vaccine was administered and deaths were recorded for 10 days.
- the challenged group been twice the size, the same level of protection would have resulted in a statistically significant survival rate.
- hexavalent vaccine in either alum or CFA.
- Booster injections of the same dose were given at 4 and 8 weeks in either alum or saline, respectively.
- ELISA titers were determined using the purified hexavalent protein as the solid phase antigen (FIG. 3 ).
- Sera from the animals that received the hexavalent vaccine in alum had antibody titers that were equal to or greater than the sera from rabbits that received the same dose in CFA.
- three rabbits were immunized i.m. with 100 ⁇ g of the hexavalent vaccine in saline alone according to the same schedule.
- ELISAs were performed on sera obtained from the three rabbits immunized with the hexavalent vaccine in alum (FIG. 4 ).
- the ELISA antigen was the purified pepsin-extracted M protein.
- the assay measures only the antibodies evoked by the hexavalent protein that react with the native M protein and not the antibodies that may be specific for the joining segments or conformations that are not present in the native M proteins.
- the hexavalent protein evoked significant levels of antibodies against each M protein represented in the vaccine construct (FIG. 4 ).
- none of the antisera contained antibodies that crossreacted with human heart tissue or kidney tissue, as determined by indirect immunofluorescence assays (data not shown).
Abstract
Description
M24-1 TS SphI | ||
5′ GGG GGG GCA TCG GTC GCG ACT AGG TCT CAG ACA GAT 3′ | (SEQ ID NO:1) | |
M24-1 BS BamHl | ||
5′ GGG GGG GGA TCC ACG TAG TTT CTC TTT AGC 3′ | (SEQ ID NO:2) | |
M5 TS BamHl | ||
5′ GGG GGG GGA TCC GCC GTG ACT AGG GGT ACA 3′ | (SEQ ID NO:3) | |
M5 BS SalI | ||
5′ GGG GGG GTC GAC CTC AGT TTT TAA CCC TTC 3′ | (SEQ ID NO:4) | |
M6 TS SalI | ||
5′ GGG GGG GTC GAC AGA GTG TTT CCT AGG GGG 3′ | (SEQ ID NO:5) | |
M6 BS NcoI | ||
5′ GGG GGG CCA TGG TAA CTT GTC ATT ATT AGC 3′ | (SEQ ID NO:6) | |
M19 TS NcoI | ||
5′ GGG GGG CCA TGG AGA GTG CGT TAT ACT AGG 3′ | (SEQ ID NO:7) | |
M19 BS PstI | ||
5′ GGG GGG CTG CAG AGA TAA CTT CTC ATT CTG 3′ | (SEQ ID NO:8) | |
M1 TS PstI | ||
5′ GGG GGG CTG CAG AAC GGT GAT GGT AAT CCT 3′ | (SEQ ID NO:9) | |
M1 BS KpnI | ||
5′ GGG GGG GGT ACC AGC TCT CTT AAA ATC TCT 3′ | (SEQ ID NO:10) | |
M3 TS KpnI | ||
5′ GGG GGG GGT ACC TTG TTA GAT CAG GTT ACA 3′ | (SEQ ID NO:11) | |
M3 BS ClaI | ||
5′ GGG GGG ATC GAT ATT TAA CTC TTG TAA CAG 3′ | (SEQ ID NO:12) | |
M24-2 TS ClaI | ||
5′ GGG GGG ATC GAT GTC GCG ACT AGG TCT CAG 3′ | (SEQ ID NO:13) | |
M24-2 BS HindIII | ||
5′ GGG GGG AAG CTT TTA CTT ACG TGC CTC TAA TTC 3′ | (SEQ ID NO:14) |
TABLE 1 |
Protective immunogenicity of the hexavalent vaccine in mice that were |
challenged i.p. with |
#Dead/#Survived of Mice Challenged (% survival) |
| Type | 24 | |
|
Immunized mice | ||||
0/10 (100) | 4/6 (60) | 4/16 (80) p = .0002* | ||
Control mice | 9/1 (10) | 7/3 (30) | 16/4 (20) | |
*p value was calculated using the Fisher exact test. |
TABLE 2 |
Indirect bactericidal assay of rabbit antiserum against the hexavalent M |
protein vaccine. |
|
Serotype | Inoculum(CFU) | | Immune | Reduction | |
24 | 12 | 2890 | 0 | 100 |
5 | 11 | 3260 | 0 | 100 |
6 | 6 | 2640 | 0 | 100 |
19 | 6 | 1580 | 0 | 100 |
1 | 8 | 2670 | 490 | 82 |
3 | 11 | 1720 | 10 | 99 |
Claims (34)
Priority Applications (4)
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US09/151,409 US6716433B1 (en) | 1997-09-12 | 1998-09-10 | Group a streptococcal vaccines |
US10/759,600 US7255863B2 (en) | 1997-09-12 | 2004-01-16 | Group A streptococcal vaccines |
US10/780,106 US7402316B2 (en) | 1997-09-12 | 2004-02-17 | Group A streptococcal vaccines |
US12/163,721 US20090035259A1 (en) | 1997-09-12 | 2008-06-27 | Group a streptococcal vaccines |
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US5863597P | 1997-09-12 | 1997-09-12 | |
US09/151,409 US6716433B1 (en) | 1997-09-12 | 1998-09-10 | Group a streptococcal vaccines |
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US10/759,600 Division US7255863B2 (en) | 1997-09-12 | 2004-01-16 | Group A streptococcal vaccines |
US10/780,106 Continuation US7402316B2 (en) | 1997-09-12 | 2004-02-17 | Group A streptococcal vaccines |
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US10/759,600 Expired - Lifetime US7255863B2 (en) | 1997-09-12 | 2004-01-16 | Group A streptococcal vaccines |
US10/780,106 Expired - Fee Related US7402316B2 (en) | 1997-09-12 | 2004-02-17 | Group A streptococcal vaccines |
US12/163,721 Abandoned US20090035259A1 (en) | 1997-09-12 | 2008-06-27 | Group a streptococcal vaccines |
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US10/780,106 Expired - Fee Related US7402316B2 (en) | 1997-09-12 | 2004-02-17 | Group A streptococcal vaccines |
US12/163,721 Abandoned US20090035259A1 (en) | 1997-09-12 | 2008-06-27 | Group a streptococcal vaccines |
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US20030143245A1 (en) * | 2001-10-26 | 2003-07-31 | University Of Tennessee Research Corporation | Multivalent streptococcal vaccine compositions and methods for use |
US20040236072A1 (en) * | 2001-04-13 | 2004-11-25 | Olmsted Stephen Bruce | Surface proteins of streptococcus pyogenes |
US20040236087A1 (en) * | 2001-05-15 | 2004-11-25 | Denis Martin | Moraxella(branhamella) catarrhalis antigens |
US20050002956A1 (en) * | 2002-11-15 | 2005-01-06 | Id Biomedical Corporation Of Quebec | Vaccine |
US20050063988A1 (en) * | 1997-09-12 | 2005-03-24 | University Of Tennessee Research Foundation | Group a streptococcal vaccines |
US20050220808A1 (en) * | 2001-05-18 | 2005-10-06 | Beall Bernard W | Peptide vaccines against group a streptococci |
US20050226891A1 (en) * | 1998-03-02 | 2005-10-13 | Ades Edwin W | Multiple antigenic peptides immunogenic against Streptococcus pneumonia |
US20060210579A1 (en) * | 2000-10-27 | 2006-09-21 | Novartis Vaccines And Diagnostics, Inc. | Nucleic acids and proteins from streptococcus groups A & B |
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US20070110763A1 (en) * | 2003-08-15 | 2007-05-17 | Stephane Rioux | Polypeptides of streptococcus pyogenes |
US20070110766A1 (en) * | 1995-03-17 | 2007-05-17 | Id Biomedical Corporation | Proteinase K resistant surface protein of neisseria meningitidis |
US20080233123A1 (en) * | 2000-10-13 | 2008-09-25 | Joelle Thonnard | Polypeptide from haemophilus influenzae |
US20100183518A1 (en) * | 2006-11-30 | 2010-07-22 | Fundacao Zerbini | Vaccine Against Group A Beta Hemolytic Streptococcus And Respective Process For Obtaining Thereof |
WO2012174455A2 (en) | 2011-06-17 | 2012-12-20 | University Of Tennessee Research Foundation | Group a streptococcus multivalent vaccine |
US9289485B2 (en) | 2006-11-30 | 2016-03-22 | Luiza Guilherme Guglielmi | Therapeutic application of S. pyogenes C-terminal peptide |
US9650425B2 (en) | 2013-02-11 | 2017-05-16 | University Of Tennessee Research Foundation | Group A streptococcal M-related proteins and methods of use |
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